Rosacea is a chronic acneiform disorder affecting skin and potentially the eye. It is a syndrome of undetermined etiology characterized by both vascular and papulopustular components involving the face and occasionally the neck, scalp, ears and upper trunk. Clinical findings include mid facial erythema, telangiectasis, papules and pustules, and sebaceous gland hypertrophy. Rosacea is characterized by episodic flushing of affected areas, which can be triggered by various factors, such as consumption of alcohol, hot drinks, spicy foods or physical exercise. Facial rosacea is classified/graded in multiple clinical forms: (1) erythematotelangiectatic rosacea which is characterized by (semi-) permanent erythema and/or flushing; (2) papulopustular rosacea, characterized by presence of inflammatory lesions such as papules and pustules; (3) phymatous rosacea characterized by circumscribed permanent swelling/thickening of skin areas, typically the nose; and (4) ocular rosacea characterized by the appearance of redness in eyes and eyelids due to telangiectasias and inflammation, feeling of dryness, irritation, or gritty, foreign body sensations, itching, burning, stinging, and sensitivity to light, eyes being susceptible to infection, or blurry vision.
Rosacea occurs most commonly in adult life, between the ages of 30 and 60 years. It is very common in skin types I-II (according Fitzpatrick) and more common in Caucasians, with a prevalence of up to 5% in the U.S. and in Europe. It is estimated that from 10 to 20 million Americans have the condition.
Topical treatments for rosacea include metronidazole, azelaic acid and brimonidine tartrate. However, approved topical therapies rarely show sufficient clinical efficacy or provide only cosmetic relief for several hours. Mainstays of treatment for rosacea are the oral tetracyclines: doxycycline and minocycline. Low-dose systemic doxycycline (Oracea® resp. Oraycea®) is approved for rosacea whereas systemic minocycline is used in many cases for rosacea off-label. Minocycline is generally regarded as having less photosensitivity than doxycycline. The long-term use of systemic antibiotics is limited by potential liver toxicity, phototoxicity, drug-drug interactions and development of antibacterial resistance. Hence, an efficacious topical tetracycline formulation is highly warranted to close this medical gap.
“Acne” is a general term that describes another very common skin disorder, which afflicts many people. The prevalence of adult acne is about 3% in men and between about 11% and 12% in women. Moderate to severe acne is observed in 14% of acne patients. There are various types of acne recognized in the field, including, for example: acne vulgaris and acne conglobata. Acne vulgaris (cystic acne or simply acne) is generally characterized by areas of skin with seborrhea (scaly red skin), comedones (blackheads and whiteheads), papules (pinheads), pustules (pimples), nodules (large papules) and/or possibly scarring. Acne vulgaris may affect the face, the upper part of the chest, and the back. Severe acne vulgaris is inflammatory, but acne vulgaris can also manifest in non-inflammatory forms. Acne conglobata is a severe form of acne, and may involve many inflamed nodules that are connected under the skin to other nodules. Acne conglobata often affects the neck, chest, arms, and buttocks.
There are typically three levels of acne vulgaris: mild, moderate, and severe. Mild acne vulgaris is characterized by the presence of few to several papules and pustules, but no nodules. Patients with moderate acne typically have several to many papules and pustules, along with a few to several nodules. With severe acne vulgaris, patients typically have numerous or extensive papules and pustules, as well as many nodules.
Acne may also be classified by the type of lesion: comedonal, papulopustular, and nodulocystic. Pustules and cysts are considered inflammatory acne.
Mild to moderate acne is often treated topically, using, e.g., retinoids, benzoyl peroxide and some antibiotics. Topical retinoids are comedolytic and anti-inflammatory. Antibiotics such as tetracycline antibiotics are generally only available orally or by injection. Topical antibiotics are mainly used for their role against P. acnes. Benzoyl peroxide products are also effective against P. acnes. Unfortunately, these medications can lack satisfactory safety and efficacy profiles. In one or more embodiments, there are provided herein new and better topical anti-acne treatments and formulations.
Diagnosis of acne vulgaris may begin with a visual inspection to determine the presence and amount of comedones, papules, pustules, nodules, and other inflammatory lesions. A diagnosis of acne vulgaris may also be confirmed via clinical laboratory tests, for example, measurement of testosterone levels and performing skin lesion cultures.
Systemic antibiotics are generally indicated for moderate or severe acne. The most commonly used systemic antibiotics are tetracycline and their derivatives (e.g., minocycline). These agents have anti-inflammatory properties and they are effective against P. acnes. The more lipophilic antibiotics, such as minocycline and doxycycline, are generally more effective than tetracycline. Greater efficacy may also be due to less P. acnes resistance to minocycline.
Oral tetracycline antibiotics are generally not recommended in the treatment of minor mild acne, primarily because they cause hyper-pigmentation, erythema and dryness. Oral tetracycline therapy may induce hyperpigmentation in many organs, including nails, bone, skin, eyes, thyroid, visceral tissue, oral cavity (teeth, mucosa, alveolar bone), sclerae and heart valves. Skin and oral pigmentation have been reported to occur independently of time or amount of drug administration, whereas other tissue pigmentation has been reported to occur upon prolonged administration. Skin pigmentation includes diffuse pigmentation as well as over sites of scars or injury. Oral tetracyclines should not be used for pregnant women or nursing mothers due to teratogenic effects. Accordingly, there exists a need for topical formulations with tetracyclines which can avoid the side effects observed with oral applications.
For example, SOLODYN®, a commercially available product, is indicated to treat only inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 12 years of age or older. Adverse side effects from the use of SOLODYN® include, inter alia, diarrhea, dizziness, lightheadedness, and nausea, in addition to allergic reactions, bloody stool, blurred vision, rectal or genital irritation, and red, swollen, blistered, or peeling skin. Because of these side effects, the Food and Drug Administration added oral minocycline to its Adverse Event Reporting System (AERS), a list of medications under investigation by the FDA for potential safety issues.
Thus, a product that requires a shorter treatment period, has no or fewer adverse effects, does not cause or causes less skin irritation, and treats both inflammatory and non-inflammatory lesions would be advantageous and could improve patient compliance. There also exists a need for improved compositions and methods for treating rosacea, as well as acne. Provided herein are compositions and methods to address those needs.